Abstract Migraine affects ~15% of the adult population worldwide, and the standard treatment for acute and chronic migraine include the use of triptans, ergotamines, and analgesics. However, these medications are inadequate for the control of severe migraine, and many migraine patients suffer continuous struggle with pain. Clearly, new approaches that can effectively ameliorate acute and chronic migraine pain are urgently needed. Importantly, studies in the last decade have established that migraine pain is associated with CGRP-mediated nociception sensitivity. CGRP levels increase during a migraine attack, whereas the treatment of CGRP triggers migraine attack in sensitive patients. Due to its critical roles in inducing migraine pain, CGRP and its receptor complex, the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) have been targeted for migraine treatment. Thus far, three distinct approaches have been used to block the CGRP signaling: (1) small molecule CGRP antagonists, (2) synthetic peptide antagonists, and (3) anti-CGRP or anti-RAMP1 antibody. All of these approaches were effective in reducing migraine phenotypes in animals and/or humans. However, each of these approaches suffers efficacy or safety concerns. While existing small molecule antagonists can cause liver toxicity, the anti-CGRP and anti-RAMP1 antibodies have limited efficacy in reducing migraine attacks, perhaps due to limited access to target cells. On the other hand, there is a lack of potent peptide antagonists. Obviously, a new strategy for targeting the CGRP-mediated signaling pathway is needed to meet the medical need of migraine patients. To overcome these obstacles, we have developed a group of long-acting CGRP/RAMP1-specific peptide super-antagonists that form gels in situ in aqueous solution. Based on this exciting finding, we propose to develop and identify the most potent antagonistic analog candidates (Aim 1), and characterize the pharmacokinetics of gel depots made of the selected candidates in vivo (Aim 2). This feasibility study is needed to explore the translational potential of these newly invented super-antagonists for the treatment of chronic migraine in combination with conventional migraine agents. At the end of this study, we expect to identify a potent antagonistic analog that is ready for preclinical development and a gel depot formulation that slowly releases the analog in vivo for at least two to four weeks.